EP2586438A1 - Composé utile pour la prévention des troubles de déficit cognitif chez un nouveau-né d'une femme séropositive pour le VIH traitée par azidothymidine - Google Patents

Composé utile pour la prévention des troubles de déficit cognitif chez un nouveau-né d'une femme séropositive pour le VIH traitée par azidothymidine Download PDF

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Publication number
EP2586438A1
EP2586438A1 EP11187170.3A EP11187170A EP2586438A1 EP 2586438 A1 EP2586438 A1 EP 2586438A1 EP 11187170 A EP11187170 A EP 11187170A EP 2586438 A1 EP2586438 A1 EP 2586438A1
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Prior art keywords
carnitine
acetyl
azt
acid
treatment
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EP11187170.3A
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German (de)
English (en)
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Paola Casolini
Aleardo Koverech
Raffaella Nicolai
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

Definitions

  • the present invention relates to acetyl L-carnitine or one of its pharmaceutically acceptable salts for use in preventing cognitive deficit disorders in a new born from HIV-seropositive pregnant female who is in treatment with azidothymidine (AZT).
  • AZT azidothymidine
  • HIV Human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • HIV infection in humans is considered pandemic by the World Health Organization (WHO). From its discovery in 1981 to 2006, AIDS killed more than 25 million people. A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and exacerbating the burden of poverty. Treatment with antiretroviral drugs reduces both the mortality and the morbidity of HIV infection. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission).
  • the transmission of the virus from mother to child can occur in utero (during pregnancy), intrapartum (at childbirth), or via breast feeding. In the absence of treatment, the transmission rate up to birth between the mother and child is around 25%. ( N. Engl. J. Med.2004, 351 (3): 289-292 ).
  • Azidothymidine (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI), a type of antiretroviral drug used for the treatment of HIV and/or AIDS.
  • NRTI nucleoside analog reverse-transcriptase inhibitor
  • AZT was the first approved treatment for HIV. AZT use was a major breakthrough in AIDS therapy in the 1990s that significantly altered the course of the illness and helped destroy the notion that HIV/AIDS was a death sentence. AZT slows HIV spread significantly, but does not stop it entirely.
  • AZT highly active antiretroviral therapy
  • AZT is combined with other drugs in order to prevent mutation of HIV into an AZT-resistant form ( Biochem Pharmacol 1994, 47 (2): 155-69 ).
  • AZT is also recommended as part of a regimen to prevent mother-to-child transmission of HIV during pregnancy, labor, and delivery.
  • AZT has been shown to reduce this risk to approximately 8% when given in a three-part regimen during pregnancy, delivery and to the infant for 6 weeks after birth ( N Engl J Med 1994, 331 (18): 1173-80 ).
  • EP 0839033 relates to the use of acetyl L-carnitine in combination with nucleoside-like inhibitors of reverse transcriptase, non-nucleoside inhibitors of reverse transcriptase and inhibitors of HINT protease, for reducing ceramide levels and enhance the activity of the aforesaid antiretroviral drugs in HIV-infected patients.
  • US 6,037,372 relates to the use of acetyl L-carnitine for the therapeutic treatment or prophylaxis of glutamate-mediated disturbances or diseases selected from cancer, infection with HIV, immunodeficiencies, drug dependencies, headaches, chronic fatigue syndrome, schizophrenic disorders, epilepsy, amyotrophic lateral sclerosis and other motor neuron diseases and peripheral neuropathies, senile and presenile dementias, apoplexy and sequences thereof, cerebrovascular ischaemic diseases, decreased cerebral flow and altered cerebral metabolism, neurodegenerative diseases, Huntington's disease, Parkinson's disease, prion protein diseases, meningoencephalitis, and Chinese restaurant syndrome.
  • glutamate-mediated disturbances or diseases selected from cancer, infection with HIV, immunodeficiencies, drug dependencies, headaches, chronic fatigue syndrome, schizophrenic disorders, epilepsy, amyotrophic lateral sclerosis and other motor neuron diseases and peripheral neuropathies, senile and presenile dementias,
  • US 5192805 relates to the use of acetyl L-carnitine in the therapeutic treatment of coma.
  • EP 0808626 relates to the use of acetyl L-carnitine to produce a medicament for the treatment of Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • EP 0207011 relates to the use of some alkanoyl L-carnitines for the manufacture of a medicament for therapeutical treatment of idiopathic and induced Parkinsonism, acetyl L-carnitine is mentioned.
  • Acetyl L-carnitine is a known compound, for which the preparation process is described in US 4,254,053 .
  • acetyl L-carnitine or one of its pharmaceutically acceptable salts is useful in preventing cognitive deficit disorders in a new born from HIV-seropositive pregnant female, which are in treatment with azidothymidine.
  • salt of acetyl L-carnitine is any salt prepared by addition of an acid to acetyl L-carnitine inner salt, and which does not give rise to unwanted toxic or side effects.
  • the formation of salts by addition of an acid is well known in pharmaceutical technology.
  • Non-limiting examples of such salts are chloride, bromide, orotate, aspartate, acid aspartate, citrate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate, acid fumarate, magnesium fumarate, glycerophosphate, lactate, maleate and acid maleate, mucate, oxalate, acid oxalate, pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate, tartrate, acid tartrate, magnesium tartrate, 2-amino ethanesulphonate, magnesium 2-amino ethanesulphonate, methane-sulphonate, choline tartrate, trichloroacetate, and trifluoroacetate.
  • acetyl L-carnitine for use for preventing cognitive deficit disorders in a new born from HIV-seropositive pregnant female who is in treatment with azidothymidine.
  • Acetyl L-carnitine is preferably administered daily, at the early stage of pregnancy; in an independent, concomitant or sequential manner respect to the administration of AZT.
  • administration may be by various parenteral routes such as subcutaneous, intravenous, intradermal, intramuscular, intraperitoneal, intranasal, transdermal, oral, or buccal routes.
  • Parenteral administration can be by bolus injection or by gradual perfusion over time.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions, which may contain auxiliary agents or excipients known in the art, and can be prepared according to routine methods.
  • the acetyl L-carnitine according to the present invention is in the form of tablets, capsules, suppositories, suspensions or solutions.
  • the dosage administered will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the dosage will be tailored to the individual subject, as is understood and determinable by one of skill in the art.
  • the total dose required for each treatment may be administered by multiple doses or in a single dose.
  • the active ingredients of the present invention are familiar to operators in the medical field and already in use.
  • the therapeutically effective dose can be estimated initially either in cell culture assays, for example, of neoplastic cells, or in animal models, usually mice or rats.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • the dose of acetyl L-carnitine to be administered is from 500 mg to 4 grams/day, a preferred dose is 1-3 grams/day, the most preferred dose is 2 grams/day.
  • the precise effective dose for a human subject will depend upon the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician.
  • mice of outbred Swiss-derived strain were purchased from Charles River (Calco, Italy). Upon arrival at the laboratory, the animals were housed in an air-conditioned room (temperature 20-22°C, relative humidity 55 ⁇ 5%) with a reversed 12:12 light cycle (light on at 19.00 h, light off at 07.00 h). Water and food were available ad libitum. Females were group-housed (4 per cage) for 7 days to coordinate their estrous cycle. After that, pairs of female mice were housed with a single sexually experienced male mice.
  • GD10 On gestational day 10 (GD10), pregnant mice were randomly assigned, on the basis of the treatment received, to four groups: Saline (Control), 3'-azido-3'-deoxythimidine (AZT), acetyl L-carnitine (ALC) and AZT+ALC.
  • AZT was purchased from Sigma-Aldrich (Milano, Italy) and ALC was synthesized and provided by Sigma Tau Laboratories (Pomezia, Rome, Italy) AZT was dissolved in bidistilled water and ALC in saline.
  • the treatment consisted in the daily administration of ALC (100 mg/kg) or vehicle (saline) by subcutaneous injection (s.c.; 1.25ml/kg), from GD0 to delivery, and in the twice daily (10:00 h and 17:00 h) administration of AZT (150 mg/kg) or vehicle (water; 3.3 ml/kg) by transoral gavage, from GD10 to delivery.
  • the Control group was s.c. injected with saline and orally treated twice daily with water.
  • the AZT group was s.c. injected with saline and orally treated twice daily with AZT.
  • the ALC group was s.c. injected with ALC and orally treated twice daily with water.
  • the AZT+ALC group was s.c injected with ALC and orally treated twice daily with AZT.
  • the day of birth was defined as postnatal day 0 (PND0).
  • PND21 postnatal day 0
  • PND60 2 months of age
  • litter mates of each group were weighed at birth (PND0), after weaning (PND24) and at adult age (PND60).
  • mice were sacrificed on PND60 to assess expression of ionotropic and metabotropic glutamate receptors.
  • ionotropic receptors we assessed AMPA Glu1 and Glu2 subunit, and NMDA NR1 subunit.
  • metabotropic receptors we measured both group I mGluR1 and mGluR5 subtypes and group II mGlu2/3 subtypes. Mice were killed by decapitation and brains rapidly removed; hippocampi were dissected and stored at -80°C.
  • tissue was homogenized at 4°C with a polytron in 500 ⁇ l of 100 mM Tris buffer, containing phenylmethylsulfonyl fluoride 1 mM, leupeptin 10 ⁇ g/ml and aprotinin 10 ⁇ g/ml pH 7.2. Protein concentrations were determined using the Bradford protein assay. Thirty micrograms of protein were resuspended in sodium dodecyl sulfate (SDS)-bromophenol blue loading buffer with 0,5 M dithiothreitol.
  • SDS sodium dodecyl sulfate
  • blots were incubated overnight with rabbit anti-mGluR1a (1:1000), anti-mGluR5 (1:1000), anti-mGluR2/3 (1:1000), anti-NR1 (1:1000) and mouse antiGlu1 and antiGlu2 (1:500) (Upstate Biotechnology, Lake Placid, NY, USA) in blocking solution at 4°C. After incubation with the primary antibody, the blots were incubated with horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse antibodies (1:5000; Amersham Bioscience) for 1h at room temperature (21°C ⁇ 2).
  • the blots were probed with an anti-actin serum (1:1000; Sigma, St Louis, MO, USA) overnight at 4°C. Subsequently, blots were incubated with horseradish peroxidase-conjugated goat anti-mouse antibodies (1:5000; Amersham Bioscience) for 1h at room temperature. Immunoreactive bands were visualized with an enhanced chemiluminescence system (Amersham Biosciences).
  • mice at PND60 were tested in the Morris water maze for their spatial learning ability.
  • the apparatus consisted of a circular pool (diameter 110 cm, height 60 cm) located in a test room with white walls with several cues on them.
  • the pool with its inner surface painted black, was filled to a depth of 40 cm with water (maintained at 25 ⁇ 1°C), covering an invisible (black) 10-cm square platform.
  • the platform was located approximately 0.5 cm below the surface of the water.
  • the pool was virtually divided into 4 quadrants (North, South, East, or West) and the platform placed at a fixed position in the center of the North quadrant. Subjects received, in a single-day training procedure, four four-trial sessions of training, with each session separated by 30 min.
  • Trials within each session were separated by 60 sec. On each trial, the subject was gently released in the water with its head facing the pool wall from one of quadrants. The order of the starting quadrant was changed in each session and trial. A maximum of 60 sec was allowed, during which the mouse had to find the platform, climb onto it and allowed to remain there for 10 sec. If the animal did not find the platform, it was gently guided with a grid and allowed to stay for 10 sec.
  • a video camera above the center of the pool was connected to a computerized tracking system that recorded and analyzed animal behavior (San Diego Instruments). The time of escape onto the platform and the swim speed were measured. After the last trial of the last session of training, animals were submitted to a single 60 sec "probe trial" in which the platform was removed from the pool. The animal started the probe trial in the south quadrant and the time that it swam through the north quadrant, where the platform had been previously located, provided a measure of learning accuracy in recalling the former position of the platform. A session with a visible platform was performed to assess the swimming speed of the two groups of animals.
  • Plasma corticosterone concentrations were determined by radioimmunoassay (MP Biomedicals, France). The cross-reactivity of the polyclonal corticosterone-antisera with respective related substances was negligible. The inter- and intra-assay coefficients of variance were 7% and 4%, respectively, with a detection limit of 0.01 ⁇ g/100ml.
  • the levels of the F2-isoprostane 15-F 2t -IsoP were measured in brain homogenates, as previously described (Minghetti et al., 2000). Briefly, brains were weighed and homogenized in 50 mM Tris buffer, pH 7.5 (1 mg/0.1 ml), containing the anti-oxidant 10 ⁇ M BHT to block spontaneous oxidation. Homogenates were vigorously vortexed and incubated for 5 min on ice before centrifuging at 14,000 rpm for 45 min at 4 °C. Supernatants were collected and stored at -80 °C until required.
  • 15-F 2t -IsoP (also known as 8-epi-PGF2 ⁇ ) was measured by a specific enzyme immunoassay (Cayman Chemical, Ann Arbor, MI, USA), according to the manufacturer's instructions. Detection limit was 2 pg/ml; anti-15-F2t-IsoP antibody cross-reactivity with other iso-prostaglandins was less than 0.15%.
  • Oxidized protein was detected by using an oxidized protein detection kit (OxyBlot, Chemicon International).
  • the OxyBlot provides reagents for sensitive immunodetection of carbonyl groups, which is a hallmark of the oxidation status of proteins. The procedure was performed according to manufacturer's recommendation. Briefly, 30 ⁇ g of hippocampal homogenates were derivatized with or without 2,4-dinitrophenylhydrazine (DNPH) and samples loaded onto a 12% SDS-PAGE gel.
  • DNPH 2,4-dinitrophenylhydrazine
  • proteins were electrotransferred to a nitrocellulose membrane and incubated with a primary antibody against the derivatized carbonyl groups followed by incubation with a horseradish peroxidase-conjugate goat anti-rabbit antibody.
  • the oxidized proteins were visualized by using an enhanced chemiluminescence system (Amersham Biosciences).
  • the relative optical densities were quantified using the NIH Image medical imaging software. No immunoreactivity was detected in the non-DNPH derivatized brain homogenates
  • Body weight data were analyzed separately for each age point by one-way ANOVA. Latencies to reach the platform in the Morris water maze were analyzed by three-way ANOVA for repeated measures (treatment x trial x session with repeated measures on trials and sessions). The ANOVA analyses were always followed by Fisher's LSD post-hoc comparisons. Probe trial, swimming speed, plasma corticosterone concentrations and immunoblot data were analyzed by Student's t-test. The level of significance was set at p ⁇ 0.05.
  • Table 1 the body weight of the litter mates at different age of life is described.
  • ALC per se did not modify pups' body weight at birth, but increased it on PND24 (ALC vs all other groups, p ⁇ 0.05 Fisher's LSD post-hoc).
  • mean body weight was comparable in the four experimental groups.
  • mGluR1a receptors in AZT+ALC group showed a trend to increase (although not statistical significant) in respect to AZT animals and did not differ from control group. Therefore, ALC treatment could be able to prevent the AZT-induced reduction of mGluR1a receptor expression.
  • Fig. 3 protein expression relative to ionotropic receptors is shown.
  • the AMPA Glu2 subunit Figure 3B
  • NMDA NR1 subunit Figure 4
  • Figure 5A shows the latencies to reach the hidden platform throughout the four sessions of the MWM.
  • Post-hoc analysis showed that subjects that have received prenatal AZT treatment display a significant increase in escape latency in respect to the control group in all the four sessions.
  • the AZT+ALC group has, in the 3 rd and 4 th session, escape latency comparable to the Control group, and significantly different from the AZT group, suggesting that pre-treatment with ALC improved the AZT-induced cognitive deficits.
  • ALC treatment alone did not modify learning abilities.
  • 15-F2t-Isop a reliable and sensitive marker of oxidative stress
  • 15-F2t-Isop levels showed a trend to increase in homogenates from AZT prenatally-treated pups, but not in those from ALC or ALC+AZT groups.

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EP11187170.3A 2011-10-28 2011-10-28 Composé utile pour la prévention des troubles de déficit cognitif chez un nouveau-né d'une femme séropositive pour le VIH traitée par azidothymidine Withdrawn EP2586438A1 (fr)

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EP11187170.3A EP2586438A1 (fr) 2011-10-28 2011-10-28 Composé utile pour la prévention des troubles de déficit cognitif chez un nouveau-né d'une femme séropositive pour le VIH traitée par azidothymidine

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EP11187170.3A EP2586438A1 (fr) 2011-10-28 2011-10-28 Composé utile pour la prévention des troubles de déficit cognitif chez un nouveau-né d'une femme séropositive pour le VIH traitée par azidothymidine

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254053A (en) 1978-07-10 1981-03-03 Claudio Cavazza Process for manufacturing D camphorate of L carnitinamide and D camphorate of D carnitinamide
EP0207011A2 (fr) 1985-06-11 1986-12-30 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de quelques alkanoyl L-carnitines pour l'obtention d'un médicament pour le traitement thérapeutique du parkinsonisme idiopathique ou provoqué
US5192805A (en) 1991-01-04 1993-03-09 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of acetyl l-carnitine in the therapeutic treatment of coma
WO1997005864A2 (fr) * 1995-08-03 1997-02-20 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Utilisation de la l-cartinine et de ses derives dans le but de reduire les niveaux de ceramides et de potentialiser l'effet antiretroviral
WO1997034596A1 (fr) * 1996-03-15 1997-09-25 Mendes S.R.L. Application d'une alcanoyl-l-carnitine au traitement de maladies dues aux glutamates
EP0808626A1 (fr) 1996-05-24 1997-11-26 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de l'acétyl-L-carnitine pour le traitement de la maladie d'Alzheimer présénile
US20100273733A1 (en) 2009-04-28 2010-10-28 Fabunan Ruben G HIV Treatment

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254053A (en) 1978-07-10 1981-03-03 Claudio Cavazza Process for manufacturing D camphorate of L carnitinamide and D camphorate of D carnitinamide
EP0207011A2 (fr) 1985-06-11 1986-12-30 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de quelques alkanoyl L-carnitines pour l'obtention d'un médicament pour le traitement thérapeutique du parkinsonisme idiopathique ou provoqué
US5192805A (en) 1991-01-04 1993-03-09 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of acetyl l-carnitine in the therapeutic treatment of coma
WO1997005864A2 (fr) * 1995-08-03 1997-02-20 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Utilisation de la l-cartinine et de ses derives dans le but de reduire les niveaux de ceramides et de potentialiser l'effet antiretroviral
EP0839033A2 (fr) 1995-08-03 1998-05-06 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de la l-cartinine et de ses derives dans le but de reduire les niveaux de ceramides et de potentialiser l'effet antiretroviral
WO1997034596A1 (fr) * 1996-03-15 1997-09-25 Mendes S.R.L. Application d'une alcanoyl-l-carnitine au traitement de maladies dues aux glutamates
US6037372A (en) 1996-03-15 2000-03-14 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of an alkanoyl-L-carnitine for the treatment of glutamate mediated diseases
EP0808626A1 (fr) 1996-05-24 1997-11-26 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de l'acétyl-L-carnitine pour le traitement de la maladie d'Alzheimer présénile
US20100273733A1 (en) 2009-04-28 2010-10-28 Fabunan Ruben G HIV Treatment

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BIOCHEM PHARMACOL, vol. 47, no. 2, 1994, pages 155 - 69
DALAKAS M C ET AL: "ZIDOVUDINE-INDUCED MITOCHONDRIAL MYOPATHY IS ASSOCIATED WITH MUSCLE CARNITINE DEFICIENCY AND LIPID STORAGE", ANNALS OF NEUROLOGY, JOHN WILEY AND SONS, BOSTON, US, vol. 35, no. 4, 1 April 1994 (1994-04-01), pages 482 - 487, XP000617927, ISSN: 0364-5134, DOI: 10.1002/ANA.410350418 *
N ENGL J MED, vol. 331, no. 18, 1994, pages 1173 - 80
N. ENGL. J. MED., vol. 351, no. 3, 2004, pages 289 - 292
SEMINO-MORA M C ET AL: "EFFECT OF L-CARNITINE ON THE ZIDOVUDINE-INDUCED DESTRUCTION OF HUMAN MYOTUBES. PART I: L-CARNITINE PREVENTS THE MYOTOXICITY OF AZT IN VITRO", LABORATORY INVESTIGATION, NATURE PUBLISHING GROUP, THE UNITED STATES AND CANADIAN ACADEMY OF PALHOLOGY, INC, vol. 71, no. 1, 1 July 1994 (1994-07-01), pages 102 - 112, XP000617940, ISSN: 0023-6837 *
SIMONE DE C ET AL: "CARNITINE DEPLETION IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS WITH AIDS: EFFECT OF ORAL L-CARNITINE", AIDS, PHILADELPHIA,PA, US, vol. 8, no. 5, 1 May 1994 (1994-05-01), pages 655 - 660, XP000617930 *
SIMONE DE C ET AL: "HIGH DOSE L-CARNITINE IMPROVES IMMUNOLOGIC AND METABOLIC PARAMETERS IN AIDS PATIENTS", IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY, INFORMA HEALTHCARE, US, vol. 15, no. 1, 1 January 1993 (1993-01-01), pages 1 - 12, XP000617932, ISSN: 0892-3973 *

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